Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) drives migration and progression of T-cell acute lymphoblastic leukemia in vitro and in vivo

M Wei,M G Haney,M G Haney,D R Rivas,J S Blackburn,J S Blackburn

doi:10.1038/s41389-020-0192-5

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer. There are no immunotherapies and few molecularly targeted therapeutics available for treatment of this malignancy. The identification and characterization of genes and pathways that drive T-ALL progression are critical for the development of new therapies for T-ALL. Here, we determined that the protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) plays a critical role in T-ALL initiation and progression by promoting leukemia cell migration. PRL-3 is highly expressed in patient T-ALL samples at both the mRNA and protein levels compared to normal lymphocytes. Knock-down of PRL-3 expression using short-hairpin RNA (shRNA) in human T-ALL cell lines significantly impeded T-ALL cell migration capacity in vitro and reduced their ability to engraft and proliferate in vivo in xenograft mouse models. Additionally, PRL-3 overexpression in a Myc-induced zebrafish T-ALL model significantly accelerated disease onset and shortened the time needed for cells to enter blood circulation. Reverse-phase protein array (RPPA) and gene set enrichment analysis (GSEA) revealed that the SRC signaling pathway is affected by PRL-3. Immunoblot analyses validated that manipulation of PRL-3 expression in T-ALL cells affected the SRC signaling pathway, which is directly involved in cell migration, although Src was not a direct substrate of PRL-3. More importantly, T-ALL cell growth and migration were inhibited by small molecule inhibition of PRL-3, suggesting that PRL-3 has potential as a therapeutic target in T-ALL. Taken together, our study identifies PRL-3 as an oncogenic driver in T-ALL both in vitro and in vivo and provides a strong rationale for targeted therapies that interfere with PRL-3 function.

Highlights

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, representing 10–15% of pediatric and 25% of adult ALL cases[1]
Compared to other types of leukemia, T-ALL is urgently lacking immunotherapies or molecularly targeted therapies, which correlates with a worse prognosis for patients who fail traditional chemotherapy regimens
We found phosphatase of regenerating liver 3 (PRL-3) was highly expressed in T-ALL patient samples and cell lines, consistent with studies reporting PRL-3 upregulation in solid tumors[42] and B-ALL43

Summary

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, representing 10–15% of pediatric and 25% of adult ALL cases[1]. The treatment of T-ALL lags behind that of B-cell ALL (B-ALL) and other leukemia subtypes in regard to both availability of immunotherapies and the development of molecular targeted therapies[2]. More effective and selective treatment strategies are critically needed for T-ALL. Protein phosphatases cooperate with kinases to precisely maintain appropriate protein phosphorylation and have important roles in modulating the strength and duration of signaling events, critical for normal cellular functions. While kinase inhibitors have achieved significant success in clinic[6], phosphatases are underexplored as drug targets[7,8], largely due to the

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Conclusion